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Review
. 2022 Dec 2;17(1):421.
doi: 10.1186/s13023-022-02577-2.

Estimation of ENPP1 deficiency genetic prevalence using a comprehensive literature review and population databases

Lauren M Chunn  1 , Jeffrey Bissonnette  1 , Stefanie V Heinrich  1 , Stephanie A Mercurio  1 , Mark J Kiel  2 , Frank Rutsch  3 , Carlos R Ferreira  4
Affiliations
Review

Estimation of ENPP1 deficiency genetic prevalence using a comprehensive literature review and population databases

Lauren M Chunn et al. Orphanet J Rare Dis. .

Abstract

Background: ENPP1 Deficiency-caused by biallelic variants in ENPP1-leads to widespread arterial calcification in early life (Generalized Arterial Calcification of Infancy, GACI) or hypophosphatemic rickets in later life (Autosomal Recessive Hypophosphatemic Rickets type 2, ARHR2). A prior study using the Exome Aggregation Consortium (ExAC)-a database of exomes obtained from approximately 60,000 individuals-estimated the genetic prevalence at approximately 1 in 200,000 pregnancies.

Methods: We estimated the genetic prevalence of ENPP1 Deficiency by evaluating allele frequencies from a population database, assuming Hardy-Weinberg equilibrium. This estimate benefitted from a comprehensive literature review using Mastermind ( https://mastermind.genomenon.com/ ), which uncovered additional variants and supporting evidence, a larger population database with approximately 140,000 individuals, and improved interpretation of variants as per current clinical guidelines.

Results: We estimate a genetic prevalence of approximately 1 in 64,000 pregnancies, thus more than tripling the prior estimate. In addition, the carrier frequency of ENPP1 variants was found to be highest in East Asian populations, albeit based on a small sample.

Conclusion: These results indicate that a significant number of patients with ENPP1 Deficiency remain undiagnosed. Efforts to increase disease awareness as well as expand genetic testing, particularly in non-European populations are warranted, especially now that clinical trials for enzyme replacement therapy, which proved successful in animal models, are underway.

Keywords: Autosomal recessive hypophosphatemic rickets type 2 (ARHR2); ENPP1 deficiency; Generalized arterial calcification of infancy (GACI); Population database; Prevalence.

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Conflict of interest statement

L.M.C., J.B, S.V.H., S.A.M., and M.J.K are all full-time employees of Genomenon, Inc. C.R.F. reports a collaboration with Inozyme Pharma Inc. as part of a Cooperative Research and Development Agreement (CRADA).

Figures

Fig. 1
Fig. 1
Inclusion/Exclusion of Variants in ENPP1. The number of variants included or excluded, along with the reason, is displayed. Loss of function (LOF) variants include start loss, nonsense, frameshift, and canonical splice site variants. VUS Variant of Undetermined Significance
Fig. 2
Fig. 2
Contribution of Individual ENPP1 Variants to the Genetic Prevalence Estimate
Fig. 3
Fig. 3
Population-Specific Carrier Frequencies of ENPP1 Variants. The carrier frequency was calculated using the Hardy–Weinberg equilibrium equation and the sum of the allele frequencies of the specified variants. Known Pathogenic/Likely Pathogenic: variants that were classified as Pathogenic/Likely Pathogenic by ACMG/AMP. Presumed Pathogenic LOF: start loss, nonsense, frameshift, and canonical splice site variants that were found in gnomAD but not the published literature. Presumed Pathogenic Missense: predicted damaging missense variants that were found in gnomAD but not the published literature
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